Pharmaceutical suspension composition

ABSTRACT

An aqueous oral liquid pharmaceutical composition system with reduced propensity for agglomeration and phase separation which is particularly amendable to the suspension of one or more pharmaceutical actives that are substantially insoluble in water. The oral liquid pharmaceutical composition may further comprise pharmaceutical actives that are soluble in water and dissolve in the aqueous medium. In the composition of the invention both suspended and any dissolved active agents are distributed homogeneously.

FIELD OF INVENTION

An aqueous, oral liquid pharmaceutical composition comprising asuspension of a pharmaceutically active compound or compounds isprovided. The composition is particularly well suited for the relief ofcold, cough, flu, fever, headache, pain, body ache, migraine and allergysymptoms in pediatric patients.

BACKGROUND OF INVENTION

Orally administered pharmaceutical compositions are provided to patientsin many dosage forms, including solid forms such as capsules, caplets ortablets and liquid forms such as solutions, emulsions or suspensions.Pharmaceutical compositions administered in solid form are usuallyintended to be swallowed whole. Children, older persons and many otherpersons including disabled or incapacitated patients often have troubleswallowing tablets or capsules. For many such patients, includingpediatric and geriatric patients, a liquid dose form is preferablebecause of the ease with which it may be swallowed.

Pharmaceutically acceptable liquid excipient suspension systems havebeen described in the literature. For example, in U.S. Pat. No.5,759,579, Singh et al. describe a xanthan gum andhydroxypropylmethylcellulose liquid excipient for suspending solidpharmaceutically active compounds. Blase et al. in U.S. Pat. Nos.5,272,137 and 5,409,907 describe and claim a liquid suspension systemfor the substantially water soluble pharmaceutical active,acetaminophen.

Although such suspensions are known, the known systems frequentlymanifest the undesirable properties of irreversible agglomeration and/orphase separation particularly if a pharmaceutical active with a limitedsolubility in water is used. Hence, it would be desirable to have aliquid excipient suspension system with reduced propensity foroccurrence of irreversible agglomeration and/or phase separation that issuitable for the suspension of pharmaceutical actives substantiallyinsoluble in water.

SUMMARY OF THE INVENTION

The invention is directed to an oral liquid pharmaceutical compositioncomprising a suspending system which comprises in a preferred embodimentan aqueous composition, which includes about 0.1 g/100 mL to about 1.0g/100 mL xanthan gum and about 0.5 g/100 mL to about 3.0 g/100 mLmicrocrystalline cellulose/carboxymethylcellulose sodium in an aqueousbase (or “aqueous medium”) and at least one pharmaceutical active (alsoreferred to herein as “at least one pharmaceutical active compound” or“at least one first pharmaceutical active”), that is substantiallyinsoluble in water (or the aqueous base). The suspending system is alsoreferred to herein as an “aqueous based suspending system” or an“aqueous composition”.

The pharmaceutical active is suspended in the aqueous composition and adensity adjusting agent is employed to balance or match the true densityof the suspended ingredients (typically the pharmaceutical active) withthe specific gravity of the suspending medium. In an exemplaryembodiment, the density adjusting agent comprises about 10 g/100 mL toabout 50 g/100 mL glycerin and about 10 g/100 mL to about 50 g/100 mLsorbitol. Alternatively, conventional sugars and/or other polyols may beused for density adjusting. However, in some embodiments it ispreferable to prepare a sugar free composition, avoiding the use ofconventional sugars. Optionally, about 0.1 g/100 mL to about 1.5 g/100mL of a surface modifying agent such as a surfactant may be included inthe liquid pharmaceutical composition. The pharmaceutical active that issubstantially insoluble in the aqueous composition may compriseibuprofen, naproxen, ketoprofen or loratadine, or a mixture thereof, forexample.

In one embodiment the pharmaceutical composition may further comprise atleast one second pharmaceutical active which is soluble in the aqueouscomposition and whereby the at least one second pharmaceutical activeremains in solution in the aqueous medium. The second pharmaceuticalactive may include one or more of pseudoephedrine, chlorpheniramine,dextromethorphan, brompheniramine, guaifenesin and diphenhydramine, forexample.

The invention provides a method of preparing an oral liquidpharmaceutical composition comprising: preparing a suspending system,suspending at least one substantially insoluble pharmaceutical active inthe suspending system and matching the true density of the substantiallyinsoluble pharmaceutical active with the specific gravity of the aqueousmedium. The suspending system may comprise an aqueous composition whichincludes about 0.1 g/100 mL to about 0.5 g/100 mL xanthan gum and about0.5 g/100 mL to about 3.0 g/100 mL microcrystallinecellulose/carboxymethylcellulose sodium and an aqueous medium. In someembodiments the method may further comprise dissolving at least onesoluble pharmaceutical active in the aqueous medium and/or adding asurface modifying agent to the pharmaceutical composition.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides an oral (and aqueous) liquid pharmaceuticalcomposition system with reduced propensity for irreversibleagglomeration and phase separation and is particularly amenable to thesuspension of one or more pharmaceutical actives that are substantiallyinsoluble in water. The oral liquid pharmaceutical composition mayfurther comprise pharmaceutical actives that are soluble in water andwhich dissolve in the aqueous medium. In the composition of theinvention both suspended and any dissolved components of the compositionare distributed substantially homogeneously. The pharmaceuticalcomposition comprises a suspending system, one or more suspendedpharmaceutical actives and a density adjusting agent. The suspendingsystem is based on a thixotropic gum system in an aqueous medium wheresufficient shear (upon shaking) permits mobility of the suspension. Inone preferred embodiment, the suspending system comprises xanthan gumand microcrystalline cellulose/carboxymethylcellulose sodium in anaqueous base. This combination yields thixotropic properties such thatthe viscosity of the undisturbed base increases over time. Such increasein viscosity is believed to facilitate minimization of the migration ofthe suspended active (or actives) upon storage over time. Upon shear(shaking), the viscosity decreases to allow easy dispensing of the drugproduct.

Additionally, the invention further offers the advantage that it ispreferably formulated using polyols. The inventors believe, withoutwishing to be bound to the theory, that the use of polyols facilitatesstability in the suspension by equilibrating the true density of thesuspended ingredients with the specific gravity of the suspendingmedium. This is believed to minimize the migration of suspendedpharmaceutical active over time. The preferred polyols for use in thepractice of the invention are a mixture of glycerin and sorbitol. Thesorbitol may be in pure form or a sorbitol solution, such as a 70%sorbitol in water solution, for example. Likewise pure glycerin, or aglycerin in water solution, such as 96% glycerin in water may be used.Conventional sugars, such as cane sugar or sucrose, fructose, or cornsyrup alone or in combination with other sugars and/or polyols may beused as the density adjusting agent. However, in embodiments intendedfor administration to a young child or diabetic geriatric patient,avoidance of conventional sugars is preferable.

In some embodiments surface modifying agents, such as a surfactant, areused in the pharmaceutical composition to modify the surface of thesuspended components. Such surface modification is believed tofacilitate diminished irreversible aggregation of the suspendedparticles.

The aqueous-based suspending system may be used to suspend one or morepharmaceutically active compounds which are substantially insoluble inwater or the aqueous medium. In some embodiments the aqueous suspendingsystem may suspend one or more substantially insoluble pharmaceuticalactive compounds and further comprise one or more other pharmaceuticallyactive compounds which are soluble in water and which are dissolved inthe aqueous medium. In the pharmaceutical composition of the inventionthe pharmaceutical active compounds (i.e., active ingredients), both thesuspended substantially insoluble active ingredients and any solubleactive ingredients dissolved in the aqueous medium, are distributed toform a substantially homogeneous distribution of active ingredients inthe pharmaceutical composition.

As used in this description and the appended claims, a pharmaceuticalactive that is substantially insoluble in the aqueous compositionincludes Ibuprofen, Ketoprofen, Naproxen, Celecoxib, Rofecoxib,Valdecoxib, Nabumetone, Glimepiride, Diclofenac, Piroxicam andMeloxican. For pharmaceutical actives not specified on this list apharmaceutical active substantially insoluble in the aqueous compositionmeans a pharmaceutical active designated as relatively insoluble orinsoluble in water by the Merck Index.

A pharmaceutical active designated to be soluble in the aqueouscomposition includes Fexofenadine (HCl), Chlorpheniramine (maleate),Brompheniramine (maleate), Diphenhydramine (HCl, Citrate), Cetirizine(HCl), Carbinoxamine (maleate), Loratadine, Desloratadine, Guaifenesin,Pseudoephedrine (HCL, Sulfate), Phenylpropanolamine (HCl), Ephedrine(HCl, Sulfate), Dextromethorphan (HBr), Codine (Phosphate) andHydrocodone (bitartrate). For pharmaceutical actives not specified onthis list, soluble pharmaceutical active means a pharmaceutical activeindicated to be soluble in water by the Merck Index.

Unless otherwise specified, amounts designated in g/100 mL means gramsper 100 milliliters of the pharmaceutical composition. For example, 10g/100 mL ibuprofen means 10 g of ibuprofen in 100 mL of the oral liquidpharmaceutical composition. A designation of mg/5 mL means milligramsper 5 milliliters of the pharmaceutical composition. For example, adesignation of 10 mg/5 mL ibuprofen means 10 mg of ibuprofen would befound in 5 milliliters of the composition. The preferred dosage unit is5 mL, to be administered to the patient as a single dosage unit ormultiples thereof, based on age and weight.

The term “medium density matching” (or “density matching”) meansbalancing the true density of the suspended components (ingredients) inthe composition with the specific gravity of the suspending medium.Density matching is accomplished using a “density adjusting agent” whichmay be comprised of one or more components. Typically, the desiredamount of suspended component and its density is determined and theamount of density adjustment agent needed to adjust the specific gravityof the medium to match the density of the suspended compound isdetermined by calculation. Calculations of density and specific gravityare well known to those skilled in the art. In some instances it isdesirable to make density and specific gravity measurements, which arefamiliar to those skilled in the art, and use the information obtainedto experimentally correct the amounts of components in the densityadjusting agent and/or amount of water to account for deviation betweentheoretical amounts calculated and actual properties manifested by thecomposition.

In one exemplary embodiment the density matching is accomplished usingthe density adjusting agent of sorbitol, or a sorbitol/water solution,and glycerin, or a glycerin/water solution, in combination withadjusting the amount of water in the composition. For a representativeexample in which ibuprofen was the substantially insolublepharmaceutically active agent, the desired density matching was achievedusing a ratio of water: sorbitol (70% solution in water): glycerin (96%in water) of about 5.6:2:3.

In some embodiments propylene glycol may be used in combination withsorbitol and/or glycerin for density balancing. Although polyols otherthan conventional sugars are preferred in some embodiments of theinvention, conventional sugars, mixtures of sugars or mixtures of sugarswith other polyols may be used in the invention. The “density adjustingagent” comprises the component or components (typically one or morepolyols), excluding water, added to achieve density matching.

“Microcrystalline cellulose/carboxymethylcellulose sodium” means a driedcoprecipitated microcrystalline of cellulose and sodiumcarboxymethylcellulose. Microcrystallinecellulose/carboxymethylcellulose sodium is a typical example of acoprecipitate in microcrystalline cellulose which may be used in thepractice of the invention.

The suspending system of the invention is an aqueous based systemincluding xanthan gum and/or microcrystallinecellulose/carboxymethylcellulose sodium incorporated therein. Whileeither xanthan gum or microcrystalline cellulose/carboxymethylcellulosesodium may be used alone in the practice of the invention, in apreferred embodiment the combination is used. Xanthan gums suitable foruse in the present invention are high molecular weight polysaccharidessuch as the xanthan gum produced by Xanthamonas capestris, for example.Xanthan gum is an article of commerce and is available, for example,from manufacturers such as: Rhodia, Inc. under the brand name Rhodigel™and from Kelco™, a division of Merck. Rhodigel™ 80 Pharm Grade isexemplary of one specific commercial product suitable for use in thepractice of the invention.

The xanthan gum is present in the liquid pharmaceutical composition inan amount of about 0.1 g/100 mL to about 1.0 g/100 mL. More preferablythe xanthan gum is present in an amount of about 0.1 g/100 mL to about0.3 g/100 mL and most preferably about 0.2 g/100 mL xanthan gum is used.It is preferable that the gum be dispersed in glycerin and hydrated inwater prior to the addition of other components to the gum system.

A microcrystalline cellulose/carboxymethylcellulose sodium suitable foruse in the practice of the invention is a coprecipitatedmicrocrystalline cellulose and sodium carboxymethylcellulose. It ispreferable that the microcrystalline cellulose/carboxymethylcellulosesodium comprises sodium carboxymethylcellulose in the range of fromabout 8 weight percent to about 19 weight percent and more preferablyabout 8 to about 15 weight percent sodium carboxymethylcellulose.Microcrystallinecellulose/carboxymethylcellulose sodium is commerciallyavailable, e.g., from FMC under the trademark Avicel™. Suitable Avicels™include but are not limited to Avicel™ CL-611; Avicel™ RC-581; andAvicel™ RC-591. Avicel™ CL-611 is the preferred Avicel™ for use in thesuspending system.

The oral pharmaceutical composition preferably comprises about 0.5 g/200mL to about 3.0 g/100 mL, more preferably about 1 g/100 mL to about 2g/100 mL, and most preferably about 1.5 g/100 mL microcrystallinecellulose/carboxymethylcellulose sodium. When used in combination withxanthan gum, it is preferable that the weight of microcrystallinecellulose/carboxymethylcellulose sodium used be about 5 to about 10times that of the weight of xanthan gum used and more preferable thatthe weight of microcrystaline cellulose/carboxymethylcellulose sodium beabout 7.5 times that of the weight of xanthan gum when used incombination.

The pharmaceutically active compounds useful in the practice of thepresent invention include non-steroidal anti-inflammatory drugs(NSAIDS), antihistamines, decongestants, antitussives, expectorants andanalgesic drugs such as acetaminophen and phencetin. Amounts ofpharmaceutically active compounds incorporated are conventional dosagesknown to those skilled in the art. Further, for pharmaceuticalcompositions intended for use in the United States, amounts ofpharmaceutical actives are preferably in compliance with applicable FDAregulation regarding dosage of such compounds.

Non-steroidal anti-inflammatory drugs (NSAIDS) which may be used in thepractice of the invention include, but are not limited to: propionicacid derivatives such as ibuprofen, naproxen, ketoprofen, flurbiprofen,fenoprofen, suprofen, fluprofen and fenbufen; acetic acid derivativessuch as tolmetin sodium, zomepirac, sulindac, and indomethacin; fenamicacid derivatives such as mefenamic acid and meclofenamate sodium;biphenyl carboxylic acid derivatives such as diflunisal and flufenisaland oxicams such as piroxicam, sudoxicam and isoxicam.

Antihistamines useful in the practice of the present invention (alongwith their preferred salt form) include, but are not limited to,chlorpheniramine (maleate), brompheniramine (maleate);dexchlorpheniramine (maleate), dexbrompheniramine (maleate),triprolidine (HCl), diphenhydramine (HCR), doxylamine (succinate),tripelenamine (HCl), cyproheptatine (HCl), bromodiphenhydrarine (HCl),phenindamine (tartrate), pyrilamine (maleate, tannate), azatadine(maleate); acrivastine, astemizole, azelastine, cetirizine, ebastine,fexofenadine, ketotifen, carbinoxamine (maleate), desloratadine,loratadine, mizolastine and terfenadine.

Antitussives useful in the practice of the present invention (along withtheir preferred salt form) include, but are not limited to, caramiphen(ediylate), dextromethorphan (HBr), codeine (phosphate, sulfate) andHydrocodone.

Decongestants useful in the practice of the invention (along with theirpreferred salt form) include, but are not limited to, pseudoephedrine(HCl), Ephedrine (HCl, Sulfate), phenylephrine (bitartarate, tannate,HBr, HCl, and phenylpropenolamine (HCl).

Expectorants which may be used in the practice of the invention (alongwith their preferred salt form) include but are not limited to terpinhydrate, guaifenesin (glycerol, guaiacolate), potassium (iodide,citrate) and potassium guaicolsulfonate.

Cox 2 inhibitors which may be used in the practice of the inventioninclude Celecoxib, Rofecoxib and Valdecoxib.

Other Pharmaceutical actives which are substantially insoluble and maybe suspended in the suspending system of the invention includenabumetone, glimepiride, diclofenac, piroxicam and meloxican.

Of the pharmaceutically active compounds described above, those whichare particularly preferred are set forth below along with preferredranges for their inclusion into the claimed pharmaceutical composition.

Ibuprofen may be used in amounts of up to about 3 grams per 100 mL.Preferably ibuprofen is present in amounts of between about 1 g/100 mLand about 3 g/100 mL. Most preferably, ibuprofen is present in amountsof about 2 g/100 mL of the pharmaceutical composition.

Naproxen may be used in amounts of about 1 g/100 mL to about 5 g/100 mLof the pharmaceutical composition. Preferably naproxen, when used in thepharmaceutical composition, is present in amounts of between about 2g/100 mL and about 3 g/100 mL of the pharmaceutical composition.

Chlorpheniramine may be used in the pharmaceutical composition inamounts between about 0.01 g/100 mL and about 0.05 g/100 mL. Preferablychlorpheniramine, when used in the pharmaceutical composition, ispresent in the amount of about 0.01 g/100 mL to 0.03 g/100mL.

Pseudoephedrine may be used in the pharmaceutical composition in amountsbetween about 0.1 g/100 mL and about 0.6 g/100 mL of the suspension.Preferably, pseudoephedrine, when used in the composition, is present inamounts of about 0.2 g/100 mL to about 0.4 g/100 mL of thepharmaceutical composition.

Chlorpheniramine maleate may be used in the pharmaceutical composition,preferably in the amount of about 0.01 g/100 mL to about 0.03 g/100 mL.

Brompheniramine maleate may be used in the pharmaceutical composition,preferably in the amount of about 0.01 g/100 mL to about 0.03 g/100 mL.

Dextromethorphan HBr may be used in the pharmaceutical composition,preferably in the amount of about 0.05 g/100 mL to about 0.250 g/100 mL.

Diphenhydramine may be used in the pharmaceutical composition,preferably in an amount of about 0.10 g/100 mL to about 0.40 g/100 mL.

The pharmaceutically active compounds are preferably of N.F. (NationalFormulary) or U.S.P. (United States Pharmacopeia) grade.

Excipients known by those skilled in the art may be useful in thepractice of the present invention. Such excipients may include but arenot limited to humectants such as glycerin and propylene glycol,defoaming agents, buffers, electrolytes, preservatives such as sodiumbenzoate and disodium edetate, sweeteners, taste masking agents andvarious flavoring and coloring agents. It is preferable to use“non-sugar” sweeteners, e.g. avoidance of the use of conventional sugarssuch as cane sugar or sucrose, and corn syrup, or fructose is preferred.Preferred sweeteners include sucralose, acesulfame K, saccharin sodium,and sorbitol. To the extent that polyols are intended for use asexcipients, this use should be accounted for in the density matchinge.g., addition of polyols not accounted for in the medium densitymatching is typically not desirable.

Examples of suitable flavoring agents include, but are not limited to,natural and artificial flavors such as mints (i.e., peppermint, etc.),menthol, cinnamon, vanilla, artificial vanilla, chocolate, artificialchocolate, bubblegum, both artificial and natural fruit flavors (i.e.,cherry, grape, orange, strawberry, etc.) and combinations of two or morethereof. Flavoring agents are generally provided as a minor component ofthe suspension in amounts effective to provide palatable flavor to thecompositions. Typically, flavoring agents are present in amounts in therange of about 0 grams to about 5 grams per 100 ml of the composition.

Preservatives useful in the present invention include but are notlimited to sodium benzoate, potassium sorbate, salts of edetate (alsoknown as salts of ethylenediaminetetraacetic acid or EDTA, such asdisodium edetate) benzaldionium chloride and parabens (such as methyl,ethyl, propyl, and butyl p-hydroxybenzoic acid esters). Preservativeslisted above are exemplary, but each preservative must be evaluated onan experimental basis, in each formulation to assure compatibility andefficacy of the preservative. Methods for evaluating the efficacy ofpreservatives in pharmaceutical formulations are known to those skilledin the art. Sodium benzoate and disodium edetate are the presentlypreferred preservative ingredients.

Preservatives are generally present in amounts of up to one gram per 100ml of the pharmaceutical composition. Preferably the preservatives arepresent in amounts in the range of from about 0.1 g/100 mL to about 0.4g/100 mL of the composition. Typically, the preservative sodium benzoatewould be present in the range of about 0.2 g/100 mL to about 0.3 g/100mL of the composition. Sodium benzoate is typically used in aconcentration of about 0.25 g/100 ml of the composition.

Coloring agents may also be incorporated in the pharmaceuticalcomposition to provide an appealing color to the composition. Thecoloring agents should be selected to avoid chemical incompatibilitieswith other ingredients in the suspension. Suitable coloring agents arewell known to those skilled in the art.

Typically, water is added in the process of making the pharmaceuticalcomposition in portions with various components. During the process ofpreparation of the pharmaceutical composition, amounts of added waterare believed to be particularly important in three instances. Sufficientwater should be available when soluble active ingredient(s) and solublesalts are added to permit them to dissolve, a sufficient amount of watershould be available in combination with the density adjusting agent toachieve medium density matching, and sufficient water should beavailable to hydrate the water soluble/dispersible gums.

Preferably, the specific gravity of the liquid portion (i.e., thesuspending medium) of the suspension should be balanced with the truedensity of the suspended actives. This may be accomplished by adding adensity adjusting agent. For a typical example, a density adjustingagent comprising about 10 g/100 mL to about 50 g/100 mL glycerin andabout 10 g/100 mL to about 50 g/100 mL sorbitol may be added to thepharmaceutical composition to achieve the desired density balance. In anexemplary embodiment containing ibuprofen as a substantially insolubleactive, the desired balance was achieved using about 30 g/100 mLglycerin (96% in water) and 20 g/100 mL sorbitol (70% solution inwater). The use of the polyol, sorbitol, is preferred in someembodiments as it also offers the additional advantage of sweetening thecomposition.

It will be understood by those skilled in the art that as liquids otherthan water are included in the liquid portion of the pharmaceuticalcomposition, the amounts of the components including water used tobalance the specific gravity of the liquid portion with the true densitymay need to be adjusted to achieve the desired balance.

Optionally about 0.1 g/100 mL to 1.5 g/100 mL surfactant may be added tothe suspending system to further stabilize the pharmaceuticalcomposition. The inventors believe, without wishing to be bound to thetheory, that the surfactant modifies the surface of suspended activesand facilitates diminished irreversible aggregation of the suspendedparticles. The surfactant may be an ionic or non-ionic surfactant ormixtures thereof. Exemplary surfactants include but are not limited topolysorbates (tweens), Spans™, togats, lecithin,polyoxyethylene-polyoxypropylene block copolymers and medium chainmono/di-glycerides. In an exemplary embodiment in which ibuprofen wasthe active agent, polysorbate 80 was used in an amount of about 0.3g/100 mL.

For an exemplary embodiment of the pharmaceutical composition, the pH isabout 3.5 to about 4.5 and the disturbed viscosity (e.g. viscositymeasured after mixing under specified conditions) at 25° C. will beabout 1500 to about 4500 cps.

EXAMPLE 1

The following Example discloses a pharmaceutical composition (which is asuspension) comprising ibuprofen as a substantially insoluble active anda process for manufacturing this composition. The composition of thesuspension of Example 1 is provided in Table 1 below: TABLE 1 Componentg/100 mL Ibuprofen USP (40 micron particle size) 2.00 PseudoephedrineHC1HCl USP 0.300 Chlorpheniramine Maleate USP 0.0200 Xanthan Gum NF(Rhodigel 80 Pharma Grade) 0.200 MicrocrystallineCellulose/Carboxymethylcellulose Sodium 1.50 NF (Avicel Type CL 611)Polysorbate 80 NF 0.300 Glycerin 96% USP 30.0 Sorbitol Solution USP 70%20.0 Micronized Sucralose Powder NF 0.200 Sodium Citrate USP/FCC 0.550Sodium Benzoate NF 0.250 Edetate Disodium USP 0.0500 Citric Acid HydrousUSP 0.750 Flavor 0.360 Color 0.0025 Purified Water USP Qs 100 mL

As indicated in the header of Table 1, amounts are stated in grams per100 milliliter aliquot of the final composition. Density matching wasaccomplished by first calculating theoretical amounts of components ofdensity adjusting agent based on the density of the insoluble active andspecific gravity of the aqueous based medicine, preparing thecomposition based on calculated amounts, then making experimentalmeasurements on the composition, and making final adjustment ofcomponent amounts of density matching agents for desired matching ofspecific gravity of the medium with the true density of suspendedcomponent based on experimental measurements. Amounts of densitymatching agent components for the Example disclosed in Table 1 weredetermined using this approach prior to manufacture of the composition.

The composition of Example 1 was prepared by placing a portion of theglycerin in a first stainless steel mixing vessel equipped with variablespeed mixer and gradually adding the xanthan gum with mixing tothoroughly disperse the xanthan gum. An aliquot of water (an amount lessthan the final amount of water) was added to a second stainless steelmixing vessel (main vessel) equipped with a variable speed mixer and themicrocrystalline cellulose/carboxymethyl cellulose sodium was added withmixing to hydrate the microcrystalline cellulose/carboxymethyl cellulosesodium. The thoroughly mixed glycerin/xanthan gum and microcrystallinecellulose/carboxymethyl cellulose sodium/water dispersions were thencombined in the main vessel with mixing. Edetate disodium was then addedand mixing was continued until the composition was uniform.

Sorbitol solution (70% sorbitol in water) was placed in a thirdstainless steel vessel equipped with a mixer. Polysorbate 80 was addedto the sorbitol solution and mixed thoroughly. Ibuprofen was then addedto the sorbitol/polysorbate 80 solution and mixed thoroughly touniformly disperse the ibuprofen.

Sodium benzoate, sodium citrate, sucralose micronized powder andcoloring agents were dissolved in an aliquot of purified water and thenadded to the contents of the main vessel with mixing.

Following the addition of the sodium benzoate, sodium citrate, sucraloseand coloring agent mixture, the sorbitol/polysorbate 80/ibuprofendispersion was added to the contents of the main vessel with mixing.

Upon completion of transfer of the sorbitol/polysorbate 80/ibuprofendispersion to the main vessel and mixing of the resulting composition, acitric acid solution in purified water was prepared and added to thecontents of the main vessel.

Soluble actives, pseudoephedrine HCl and chlorpheniramine maleate inthis example, were dissolved in a water/glycerin mixture and then addedto the contents of the main vessel with mixing. Assembly of thecomposition of Example 1 was completed by adding flavor to the contentsof the main vessel and adding sufficient purified water to adjust batchvolume to the final batch size.

After the final addition of components, mixing was continued for anadditional 30 minutes with the composition being re-circulated through a40-mesh filter. The composition was de-aerated by subjecting it to avacuum prior to packaging and/or storage.

EXAMPLE 2

The composition of Example 2 is provided in Table 2 below: TABLE 2Component g/100 mL Ibuprofen USP (40 micron particle size) 2.00Pseudoephedrine HC1 USP 0.300 Dextromethorphan HBr USP 0.150 Xanthan GumNF (Rhodigel 80 Pharma Grade) 0.200 MicrocrystallineCellulose/Carboxymethyl- 1.50 cellulose Sodium NF (Avicel Type CL 611)Propyl Gallate NF (Progallin P-Drum) 0.00500 Polysorbate 80 NF 0.300Glycerin 96% USP 30.0 Sorbitol Solution USP 70% 20.0 MicronizedSucralose Powder NF 0.200 Sodium Citrate USP/FCC 0.550 Sodium BenzoateNF 0.250 Edetate Disodium USP 0.0500 Citric Acid Hydrous USP 0.750Flavor 0.334 Color 0.0300 Purified Water USP Qs 100 mL

Example 2 is prepared in a manner similar to Example 1. The propylgallate is dispersed in glycerin prior to addition of water, thencombined with the soluble actives prior to addition to the main vessel.After the addition of the soluble actives and propyl gallate to the mainvessel, flavor is then added followed by the adjustment of the finalvolume with water.

Although the foregoing invention has been described in some detail byway of illustration and examples for purposes of clarity ofunderstanding, it will be obvious that certain changes andmodifications, may be practiced within the scope of the appended claims.Modifications of the above-described modes of practicing the inventionthat are obvious to persons of skill in the art are intended to beincluded within the scope of the following claims.

1. An oral liquid pharmaceutical composition comprising: a. a suspendingsystem which comprises an aqueous composition which includes an aqueousmedium, about 0.1 g/100 mL to about 0.5 g/100 mL xanthan gum and about0.5 g/100 mL to about 3.0 g/100 mL microcrystallinecellulose/carboxymethylcellulose sodium; b. at least one firstpharmaceutical active which is substantially insoluble in the aqueouscomposition; and c. a density adjusting agent.
 2. The pharmaceuticalcomposition of claim 1 further comprising at least one secondpharmaceutical active which is soluble in the aqueous composition. 3.The pharmaceutical composition of claim 1 wherein the density adjustingagent comprises one or more polyol.
 4. The pharmaceutical composition ofclaim 1 wherein the density adjusting agent comprises one or more ofsorbitol, glycerin, propylene glycol, or a mixture thereof.
 5. Thepharmaceutical composition of claim 4 wherein the density adjustingagent comprises 10 g/100 mL to about 50 g/100 mL glycerin and about 10g/100 mL to about 50 g/100 mL sorbitol.
 6. The pharmaceuticalcomposition of claim 1 further comprising about 0.1 g/100 mL to about1.5 g/100 mL of a surface modifying agent.
 7. The pharmaceuticalcomposition of claim 1 wherein the at least one first pharmaceuticalactive is selected from the group consisting of Ibuprofen, Ketoprofen,Naproxen, Celecoxib, Rofecoxib, Valdecoxib, Nabumetone, Glimepiride,Diclofenac, Piroxicam, Meloxican and a mixture thereof.
 8. Thepharmaceutical composition of claim 1 wherein the at least one firstpharmaceutical active is selected from the group consisting ofibuprofen, naproxen, ketoprofen, loratadine and a mixture thereof. 9.The pharmaceutical composition of claim 2 wherein the at least onesecond pharmaceutical active is selected from the group consisting ofFexofenadine (HCl), Chlorpheniramine (maleate), Brompheniramine(maleate), Diphenhydramine (HCl, Citrate), Cetirizine (HCl),Carbinoxamine (maleate), Loratadine, Desloratadine, Guaifenesin,Pseudoephedrine (HCL, Sulfate), Phenylpropanolamine (HCl), Ephedrine(HCl, Sulfate), phenylephrine, Dextromethorphan (HBr), Codine(Phosphate) and Hydrocodone (bitartrate) and a mixture thereof.
 10. Thepharmaceutical composition of claim 2 wherein the at least one secondpharmaceutical active is selected from the group consisting ofpseudoephedrine, phenylephrine, chlorpheniramine, dextromethorphan,brompheniramine, diphenhydramine and a mixture thereof.
 11. Thepharmaceutical composition of claim 2 further comprising about 0.1 g/100mL to about 1.5 g/100 mL of a surface modifying agent.
 12. Thepharmaceutical composition of claim 11 wherein the surface modifyingagent is a polysorbate.
 13. An oral liquid pharmaceutical compositioncomprising: a. a suspending system which comprises an aqueouscomposition which includes an aqueous medium, about 0.1 g/100 mL toabout 1.0 g/100 mL xanthan gum and about 0.5 g/100 mL to about 3.0 g/100mL microcrystalline cellulose/carboxymethylcellulose sodium; b. at leastone first pharmaceutical active suspended in the aqueous composition; c.at least one second pharmaceutical active soluble in the aqueouscomposition; and d. a density adjusting agent.
 14. The pharmaceuticalcomposition of claim 1 wherein the at least one first pharmaceuticalactive is selected from the group consisting of Ibuprofen, Ketoprofen,Naproxen, Celecoxib, Rofecoxib, Valdecoxib, Nabumetone, Glimepiride,Diclofenac, Piroxicam, Meloxican and a mixture thereof.
 15. Thepharmaceutical composition of claim 13 wherein the at least onesuspended first pharmaceutical active is selected from the groupconsisting of ibuprofen, naproxen, ketoprofen, loratadine, and a mixturethereof.
 16. The pharmaceutical composition of claim 15 whereinibuprofen is the suspended pharmaceutical active and is present in thepharmaceutical composition in an amount of about 1 g/100 mL to about 3g/100 mL.
 17. The pharmaceutical composition of claim 13 wherein the atleast one second pharmaceutical active is selected from the groupconsisting of Fexofenadine (HCl), Chlorpheniramine (maleate),Brompheniramine (maleate), Diphenhydramine (HCl, Citrate), Cetirizine(HCl), Carbinoxamine (maleate), Loratadine, Desloratadine, Guaifenesin,Pseudoephedrine (HCL, Sulfate), phenylephrine, Phenylpropanolamine(HCl), Ephedrine (HCl, Sulfate), Dextromethorphan (HBr), Codine(Phosphate) and Hydrocodone (bitartrate) and a mixture thereof.
 18. Thepharmaceutical composition of claim 13 in which the at least one secondpharmaceutical active soluble in the aqueous composition is selectedfrom the group consisting of pseudoephredine, phenylephrine,chlorpheniramine, dextromethorphan, brompheniramine, diphenhydramine anda mixture thereof.
 19. The pharmaceutical composition of claim 18wherein the at least one second pharmaceutical active soluble in theaqueous composition includes pseudoephredrine in the amount of about 0.2g/100 mL to about 0.4 g/100 mL and chlorpheniramine in the amount ofabout 0.01 g/100 mL to about 0.03 g/100 mL.
 20. The pharmaceuticalcomposition of claim 13 wherein the density adjusting agent comprises 10g/100 mL to about 50 g/100 mL glycerin and about 10 g/100 mL to about 50g/100 mL sorbitol.
 21. The pharmaceutical composition of claim 13further comprising about 0.1 g/100 mL to about 1.5 g/100 mL of a surfacemodifying agent.
 22. The pharmaceutical composition of claim 21 whereinthe surface modifying agent is a polysorbate.
 23. An oral liquidpharmaceutical composition comprising: a. a suspending system whichcomprises an aqueous composition which includes an aqueous medium, andat least one of about 0.1 g/100 mL to about 0.5 g/100 mL xanthan gum andabout 0.5 g/100 mL to about 3.0 g/100 mL microcrystallinecellulose/carboxymethylcellulose sodium; b. at least one firstpharmaceutical active which is substantially insoluble in the aqueouscomposition; and c. a density adjusting agent.
 24. A method fortreatment of pain and discomfort associated with at least one ofheadache, body ache, cold symptoms, flu symptoms, and allergy symptomsin humans comprising the administration to a human of a safe andeffective amount of the pharmaceutical composition of claim 1, 13 or 23.25. A method of preparing an oral liquid pharmaceutical compositioncomprising: a. preparing a suspending system, including suspendedcomponents in an aqueous medium; b. suspending at least onesubstantially insoluble first pharmaceutical active in the suspendingsystem; and c. matching the true density of the at least onesubstantially insoluble first pharmaceutical active and the suspendedcomponents of the suspending system with the specific gravity of theaqueous medium.
 26. The method of claim 25 further comprisingde-aerating the composition by subjecting it to vacuum.
 27. The methodof claim 25 further comprising dissolving in the aqueous medium at leastone second pharmaceutical active soluble in the aqueous medium.
 28. Themethod of claim 26 further comprising adding a surface modifying agentto the pharmaceutical composition.